Immunomodulatory functions of neuronal guidance cues

神经元引导信号的免疫调节功能

• 批准号: 7829376
• 负责人: KATHRYN J MOORE
• 金额: $ 49.88万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7829376
• 关键词: Acute; Address; Adhesions; Angioplasty; Animal Model; Applications Grants; Area; Arterial Fatty Streak; Biochemical Genetics; Blood Cells; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cell Adhesion Molecules; Cell Communication; Cells; Cellular Stress; Chronic; Clinical Research; Complex; Cues; Data; Development; Disease; Embryonic Development; Endothelial Cells; Endothelium; Ensure; Erythrocytes; Exposure to; Family; Genes; Grant; Heart; Hematological Disease; Homeostasis; Image; Immune; Immune System Diseases; Implant; In Vitro; Inflammation; Inflammation Process; Inflammatory; Integrins; Knowledge; Lead; Leukocyte Trafficking; Leukocytes; Life; Lung; Mammals; Mediating; Microscopic; Molecular; Myeloid Cells; Nervous system structure; Neurons; Organism; Pathogenesis; Peripheral; Physiological; Play; Population; Prevention; Procedures; Process; Recruitment Activity; Regulation; Research; Resolution; Role; Semaphorin-3A; Signal Transduction; Site; Stents; Stress; Study models; Tissues; Vascular Endothelium; Work; cell motility; chemokine; cytokine; human NTN1 protein; in vivo; migration; netrin-1; neuronal guidance; novel; novel therapeutics; prevent; public health relevance; receptor; relating to nervous system; response; therapeutic target; trafficking

DESCRIPTION (provided by applicant): This application addresses broad Challenge area (04) Clinical research, and specific Challenge Topic 04-HL-103 Assess the role of leukocyte interaction with platelets, erythrocytes, and endothelium in the pathogenesis of heart, lung, and blood diseases. Cell migration plays essential roles in embryonic development and inflammation, and this process is highly regulated to ensure tissue homeostasis. The migration of blood cells and their interactions with the cells of the vasculature, have been studied for over 100 years, from microscopic examination of simple organisms, through complex biochemical and genetic studies, to high resolution imaging of immune cells in during inflammation in living mammals. These studies have provided a great understanding of the mechanisms of inflammation and have allowed the development of new therapeutics for inflammatory and immune disorders. However our knowledge of the mechanisms by which tissue homeostasis is maintained and whether immune cells are actively excluded from non-inflamed tissues in the absence of inflammation is incomplete. Similarly, we have little understanding of the signals that can drive leukocyte exit during resolution of inflammation and whether this process is defective in chronic inflammatory conditions. Recent work from our lab and others has led us to hypothesize that 'negative guidance cues' which inactivate cell migration or mediate cell repulsion, such as those described in the developing nervous system, are also employed by endothelial cells to impede inappropriate recruitment and/or accumulation of immune cells in tissues. In our preliminary data we have found that representative guidance molecules inhibit leukocyte migration in vitro, are expressed by non-inflamed endothelial cells and prevent leukocyte attachment and recruitment to tissues in vivo. However, under cell stress or following exposure to inflammatory cytokines, expression is reduced, lowering these barriers for inflammatory cell recruitment. We believe that these data represent a new paradigm for leukocyte: endothelial interactions. In this grant application, we propose to establish the role of these guidance molecules in leukocyte: endothelial cell interactions, and identify guidance molecule: receptor pairs that mediate repulsive and attractive interactions. These studies will increase our understanding of the mechanisms that lead to recruitment, retention, and exit of inflammatory cells in the vasculature and other tissues in and will provide potential therapeutic targets for modulation of leukocyte accumulation. PUBLIC HEALTH RELEVANCE: Cell migration plays essential roles in embryonic development and inflammation, and this process is highly regulated to ensure tissue homeostasis. In this challenge grant, we propose to establish a new paradigm for inflammatory cell trafficking, identifying neuronal guidance molecule: receptor pairs that mediate repulsive and attractive interactions of leukocytes with vascular endothelium.

描述（由申请人提供）：本申请涉及广泛的挑战领域（04）临床研究，具体挑战主题04-HL-103评估白细胞相互作用与血小板，红细胞和内皮的血小板相互作用在心脏，肺和血液疾病的发病机理中的作用。细胞迁移在胚胎发育和炎症中起着至关重要的作用，并且该过程受到高度调节以确保组织稳态。血细胞的迁移及其与脉管系统细胞的相互作用已经进行了100多年的研究，从对简单生物的微观检查，到复杂的生化和遗传研究，到活哺乳动物炎症期间免疫细胞的高分辨率成像。 这些研究为炎症机制提供了充分的了解，并允许开发用于炎症和免疫疾病的新疗法。 但是，我们了解维持组织稳态的机制，以及在没有炎症的情况下是否将免疫细胞被积极排除在非炎症组织之外。 同样，我们对可以在炎症解决过程中驱动白细胞出口的信号几乎没有理解，以及在慢性炎症条件下该过程是否有缺陷。我们实验室和其他实验室的最新工作使我们假设“负引导提示”使细胞迁移或介导细胞排斥（例如在发育中的神经系统中描述的）也受到内皮细胞的使用，以阻碍不适当的募集和/或组织中免疫细胞的积累。 在我们的初步数据中，我们发现代表性的引导分子在体外抑制白细胞迁移，通过非影响的内皮细胞表达，并防止白细胞的附着和募集到体内的组织。 但是，在细胞应激或暴露于炎性细胞因子后，表达降低，降低了这些障碍以供炎症细胞募集。 我们认为，这些数据代表着白细胞：内皮相互作用的新范式。在此赠款应用中，我们建议确定这些引导分子在白细胞中的作用：内皮细胞相互作用，并确定指导分子：介导排斥和有吸引力相互作用的受体对。 这些研究将提高我们对脉管系统和其他组织中炎症细胞募集，保留和退出机制的理解，并将为调节白细胞积累的潜在治疗靶标提供。 公共卫生相关性：细胞迁移在胚胎发育和炎症中起着至关重要的作用，并且该过程受到高度调节以确保组织稳态。在这项挑战补助金中，我们建议建立一个用于炎症细胞运输的新范式，鉴定神经元引导分子：受体对介导白细胞与血管内皮细胞的排斥和有吸引力的相互作用。